Abstract
Human embryonic stem cells (hESCs) can serve as a potentially limitless source of cells that may enable regeneration of diseased tissue and organs. Here we investigate the use of human embryonic stem cell-derived cardiomyocytes (hESC-CMs) in promoting recovery from cardiac ischemia reperfusion injury in a mouse model. Using microarrays, we have described the hESC-CM transcriptome within the spectrum of changes that occur between undifferentiated hESCs and fetal heart cells. The hESC-CMs expressed cardiomyocyte genes at levels similar to those found in 20-week fetal heart cells, making this population a good source of potential replacement cells in vivo. Echocardiographic studies showed significant improvement in heart function by 8 weeks after transplantation. Finally, we demonstrate long-term engraftment of hESC-CMs by using molecular imaging to track cellular localization, survival, and proliferation in vivo. Taken together, global gene expression profiling of hESC differentiation enables a systems-based analysis of the biological processes, networks, and genes that drive hESC fate decisions, and studies such as this will serve as the foundation for future clinical applications of stem cell therapies.
Highlights
Myocardial infarction is a major cause of morbidity and mortality worldwide
To understand the time course of transcriptional changes occurring in these cells, we performed Reverse transcription polymerase chain reaction (RT-PCR) analysis of Human embryonic stem cells (hESCs)-derived embryoid body (EB) as they differentiated over the course of 42 days into beating clusters (Figure 1b)
We have described the hESC-CM transcriptome within the spectrum of changes that occur between undifferentiated hESCs and fetal heart cells, and used molecular imaging to follow their survival and engraftment in the heart
Summary
The limited ability of the surviving cardiac cells to proliferate following an ischemic attack renders the damaged heart susceptible to unfavorable remodeling processes and heart failure [1]. Pharmaceutical and implantable device management of heart failure seek only to preserve existing viable myocardium after an ischemic attack, and merely slows the progression of cardiac dysfunction. Heart transplantation is the only viable treatment option for end-stage heart failure patients. To ‘‘regenerate’’ the heart and preserve cardiac function and recover lost or diseased muscle, stem cell therapy has emerged as a promising therapy for heart disease because it can provide a virtually unlimited source of cardiomyocytes, endothelial cells, and other differentiated cell types. The hope is to use these cells to replace diseased myocardium that would otherwise progress to outright failure and regenerate the heart to its former, healthy self
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